Scientists Uncover New Compounds that Could Affect Circadian Rhythm

By Eric Sauter and Mika Ono

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered a surprising new role for a pair of compounds—which have the potential to alter circadian rhythm, the complex physiological process that responds to a 24-hour cycle of light and dark and is present in most living things.

At least one of these compounds could be developed as a chemical probe to uncover new therapeutic approaches to a range of disorders, including diabetes and obesity.

The study, which was published online ahead of print by the Journal of Biological Chemistry, focuses on a group of proteins known as REV-ERBs, a superfamily that plays an important role in the regulation of circadian physiology, metabolism and immune function.

The new study shows that the two compounds, cobalt protoporphyrin IX (CoPP) and zinc protoporphyrin IX (ZnPP), bind directly to REV-ERBs.

REV-ERBs are normally regulated by heme, a molecule that binds to hemoglobin, helps transport oxygen from the bloodstream to cells and plays a role in producing cellular energy. While heme activates REV-ERB, CoPP and ZnPP inhibit it.

“These compounds are like heme, but when you swap out their metal centers their functions are different,” said Douglas Kojetin, a TSRI associate professor who led the study. “This makes us think that the key is the chemistry of the metal ion itself. Altering the chemistry of this metal center may be an opportune way to target REV-ERB for diabetes and obesity.”

Kojetin and his colleagues recently demonstrated that synthetic REV-ERB agonists, like the new compounds, reduce body weight in mice that were obese due to diet.

The first authors of the study, “Structure of REV-ERB_ Ligand-binding Domain Bound to a Porphyrin Antagonist,” are Edna Matta-Camacho of McGill University, Montreal and Subhashis Banerjee of the University of Texas Southwestern Medical Center. Other authors of the study include Travis S. Hughes and Laura A. Solt of TSRI; and Yongjun Wang and Thomas P. Burris of St. Louis University School of Medicine.

The work was supported by the National Institutes of Health (grants DK080201 and DK101871), the James and Esther King Biomedical Research Program from the Florida Department of Health (grant 1KN-09) and the State of Florida.